Identification of innate immune pathways as targets for immunomodulatory therapy in herpes simplex virus encephalitis

Infection of the brain by herpes simplex virus (HSV encephalitis) is a devastating disease associated with a mortality rate of 70% if left untreated. Even with specific antiviral therapy i.e., intravenous acyclovir, the mortality rate is still about 15% with most survivors remaining with neurological sequelae. We postulate that both virus replication in the brain and the resulting uncontrolled inflammation are responsible for such high mortality and morbidity. In the next 5 years, we will further study the types of cells responsible for the detrimental inflammation and evaluate compounds that can block the immune response in a timely manner using mouse models. In addition, we plan to set-up a more relevant experimental model for understanding the pathogenesis of HSV encephalitis using human brain 3D models derived from human stem cells (called organoids). At term, our research will benefit the management of HSV encephalitis but also potentially that of other brain viral diseases caused by West Nile virus and Zika virus.